The present invention relates to a process for producing a biochip, a substrate immobilized with a biopolymer such as DNA or a protein. More particularly, the present invention relates to a process for producing a biochip by an inkjet system, and a biochip-producing solution used in the process.
Biochips are substrates such as glass plates which are immobilized with biopolymers such as DNAs or proteins. According to a process for producing a biochip by an inkjet system, an inkjet device used for an inkjet printer is filled with a biopolymer solution for producing a biochip (a biochip-producing solution) instead of ink, to inject the biochip-producing solution on a substrate to spot a biopolymer on the substrate.
Referring to FIG. 7, the biochip-producing solution used is a DNA solution 6 containing a mixture of Tris-HCl buffer 12, EDTA chelating agent 13 and DNA 14.
FIGS. 8A to 8C are cross-sectional views for illustrating a process for producing a biochip with an inkjet device using a piezoelectric element. Hereinafter, states of the DNA solution in the inkjet device will be described with reference to FIGS. 8A to 8C. FIG. 8A shows an initial state where a tank 1 of the inkjet device 20 is filled with the DNA solution 6 as the biochip-producing solution. The DNA solution 6 is in the tank 1 and a charging path 2 of the inkjet device 20. FIG. 8B shows a state where the DNA solution 6 is injected on a plate 5. Specifically, a voltage is applied to a piezoelectric element 3 to compress the charging path 2, by which the DNA solution 6 is pushed and injected out from an injection nozzle 4 to deposit a DNA spot 8 on a plate 5 to immobilize DNA thereon. Then, the voltage applied to the piezoelectric element 3 is reduced to release the compression stress on the charging path 2 to restore the charging path 2 from the compressed state to the normal state. This operation is repeated for subsequent plates, thereby producing a plurality of biochips.
FIG. 8C shows the ending state of the injection of the DNA solution caused by a shortage of the solution. In this state, the DNA solution 6 is remaining in the tank 1 and the charging path 2 of the inkjet device 20. According to the inkjet system, the DNA solution 6 may not be injected even when it is remaining in the device because an insufficient amount of solution in the tank 1 does not produce a pressure necessary for injection from the injection nozzle 4 upon compression of the charging path 2. As a result, the injection is terminated with the DNA solution 6 remaining in the tank 1 and the charging path 2.
As described above, according to production of a biochip with an inkjet device, not the entire amount of the biochip-producing solution in the tank is used for producing the biochip. Since the biochip production terminates with the biochip-producing solution remaining in the inkjet device, the remaining biochip-producing solution will be disposed. Thus, the amount of the biochip-producing solution required in total includes an amount to be spotted on substrates and an amount that will remain in the device, which means that more than the amount of DNA solution used for spotting is necessary. For example, in order to produce 10,000 biochips with DNA spot of 0.2 nl (nanoliter), a total of 52 xcexcl (microliters) of DNA solution is necessary including 2 xcexcl for the 10,000 DNA spots and 50 xcexcl for the DNA solution to be remained in the inkjet device and disposed. According to such a conventional process, a great portion of an expensive DNA solution prepared for biochip production is unused and disposed, increasing the cost of biochips. This problem is not only the case of the inkjet system using a piezoelectric element, but it is also a problem of all types of biochip-producing devices which ejects a DNA solution on a substrate, such as an inkjet system that injects the solution by causing bubbles by heating with a heater, and an electrostatic plotter.
In view of such conventional art problem, the present invention has an objective of providing a process for producing a biochip by an inkjet system or an electrostatic plotter system, which can use a biochip-producing solution containing biopolymers such as expensive DNA without wasting it. The present invention also has an objective of providing a biochip-producing solution preferable to be used for producing a biochip by an inkjet system or an electrostatic plotter system.
The present invention accomplishes the above-mentioned objective by using a less expensive buffer solution as a solution to be remained in the inkjet-type or electrostatic-plotter-type biochip-producing device after the production. Thus, a biochip-producing solution contains a combination of a biopolymer solution such as DNA to be spotted on a substrate and a buffer solution to be remained in the device after the production. The buffer solution used has a different specific gravity from that of the biopolymer solution and thus is not mixed therewith.
By using the biochip-producing solution containing a combination of the biopolymer solution and the buffer solution, the amount of the biopolymer solution to be injected into the biochip-producing device can be reduced to a minimum amount. For example, in order to produce 10,000 biochips, the conventional inkjet system required 52 xcexcl of the DNA solution to spot 2 xcexcl of it on substrates plus 50 xcexcl of it to remain in the device. On the other hand, the present invention requires only 2 xcexcl of the DNA solution as the solution to be spotted on substrates (by replacing the 50 xcexcl of the DNA solution to be remained in the device with the buffer solution), thereby greatly reducing the amount of the DNA solution to be prepared. Since the expensive DNA solution is not wasted, great cost reduction can be realized.
According to one aspect of the invention, a biochip-producing solution comprises a first solution containing a biopolymer and a second solution having a different specific gravity from that of the first solution so that the second solution is not mixed with the first solution.
According to another aspect of the invention, a biochip-producing solution of the invention comprises a first solution containing a biopolymer and a second solution having a specific gravity lower than that of the first solution so that the second solution is not mixed with the first solution.
According to yet another aspect of the invention, a biochip-producing solution comprises a first solution containing a biopolymer, a second solution having a specific gravity lower than that of the first solution so that the second solution is not mixed with the first solution, and a third solution having a specific gravity higher than that of the first solution so that the third solution is not mixed with the first solution.
A process for producing a biochip according to the present invention comprises: putting a biochip-producing solution containing a biopolymer into an inkjet device; and injecting the biochip-producing solution from the inkjet device to a substrate to immobilize a spot of the biopolymer on the substrate, wherein the biochip-producing solution contains a first solution containing a biopolymer and a second solution having a different specific gravity from that of the first solution so that the second solution is not mixed with the first solution.
A specific gravity of a buffer solution, which is different from that of a solution containing a biopolymer (e.g., a DNA solution) is selected such that the DNA solution stays at an injected solution side followed by the buffer solution. For example, when the solution is injected downwardly from a higher place, the specific gravity of the buffer solution is lower than that of the DNA solution so that the buffer solution stays above the DNA solution. On the other hand, when the solution is injected upwardly from a lower place, the specific gravity of the buffer solution is higher than that of the DNA solution so that the buffer solution stays under the DNA solution.